Small Plasma Cells Research Articles

Epstein Barr Virus Positive Mucocutaneous Ulcer versus Classic Hodgkin Lymphoma: Challenges in Diagnosis

Abstract Introduction/Objective Epstein- Barr virus positive mucocutaneous ulcer (EBVMCU) is a clinicopathologic entity first identified in 2010. It occurs in patients with immunosuppression and presents as a well circumscribed ulceration on the oropharyngeal mucosa, skin or gastrointestinal tract. Infiltrates of atypical lymphoid cells that may have appearances similar to Diffuse Large B-cell Lymphoma (DLBCL) or Classic Hodgkin Lymphoma (CHL) are seen. Methods/Case Report A 41 year old male patient with history of HIV infection presented with hematochezia and rectal pain, underwent sigmoidoscopy and a large ulcerated mass was present at the anal verge. Polymorphic infiltrates of small lymphoid cells, eosinophils, granulocytes, plasma cells, histiocytes and scattered large atypical lymphoid cells, morphologically mimicking Reed-Sternberg cells were identified. The large atypical lymphoid cells were positive for CD30, MUM-1, BCL-6, EBER (EBV) and negative for CD3, CD15, CD20, CD45, CD79a, SOX-10. Based on lack of B-symptoms, no lymphadenopathy, superficial lesions, reduced CD4/CD8 ratio and specific location, EBVMCU was favored. Eight months later, he presented with night sweats, decreased appetite and inguinal lymphadenopathy. Lymph node excision displayed infiltrates of predominantly small lymphocytes, histiocytes, plasma cells and eosinophils. Foci of scattered large atypical cells morphologically compatible with Hodgkin/Reed Sternberg cells with focal necrosis were noted. The atypical cells were positive for CD30, PAX5 (weak), CD20 (subset), CD15 (focal), MUM-1 and EBV-EBER. CHL, Mixed Cellularity Subtype was diagnosed. Results (if a Case Study enter NA) NA Conclusion As a newer entity, we don’t know if EBVMCU can co-exist with or progress to CHL/DLBCL. Therefore, EBVMCU patients should undergo vigilant screening.

Waldenstrom's Macroglobulinemia: A Case Report

Waldenström's macroglobulinemia (WM) is a rare, slow-growing hematologic malignancy marked by elevated levels of monoclonal immunoglobulin M (IgM) and bone marrow infiltration by lymphoplasmacytic cells. This case details a 72-year-old man who, during a pre-anesthetic consultation for lumbar spinal stenosis surgery, presented with neurological symptoms, fatigue, and headaches. Examination revealed pallor, and laboratory tests indicated anemia and an elevated erythrocyte sedimentation rate. Serum protein electrophoresis identified a monoclonal IgM spike, and bone marrow aspiration showed significant infiltration by small lymphoid cells, lymphoplasmacytoid cells, and plasma cells. WM was confirmed, and the patient was treated with dexamethasone, rituximab, and cyclophosphamide, with positive follow-up progress. This case underscores the importance of considering WM in the differential diagnosis for patients with unexplained anemia and elevated IgM levels, highlighting the need for timely diagnosis and treatment to manage potential complications.

Lymphocytoma Cutis - A Case Report

Without tissue biopsy and holistic review of presentation, histology, and immunohistochemistry, lymphocytoma cutis (LC) can often be misdiagnosed as other benign conditions or malignant pathologies such as cutaneous B cell lymphoma (CBCL). A 36-year-old female presented with a two-year history of a progressive indurated, edematous plaque in the preauricular area. At presentation, the patient also had labs significant for thrombocytopenia and eosinophilia. Original treatment with topical steroids did not lead to clinical improvement of the lesions. Punch biopsy revealed reactive lymphoid hyperplasia with polyclonal lymphoid infiltrates of small lymphocytes, histiocytes, eosinophils, and plasma cells. Diagnosis of LC was made and our patient was treated with serial 5 mg intralesional triamcinolone injections. Clinical improvement was seen beginning at 2 months. Diagnosing LC can be particularly difficult as the clinical presentation is ubiquitous and can resemble several other conditions such as CBCL, cutaneous lupus erythematosus, sarcoid, or hypersensitivity reactions. Recognition of the typical histologic findings of top-heavy dermal mixed-cellular infiltrates along with polyclonal kappa and lambda hybridization on immunohistochemistry is often essential in arriving at the correct diagnosis. Following diagnosis of LC, long-term surveillance is recommended as malignant transformation is a possibility.

Generation of circulating autoreactive pre-plasma cells fueled by naive B cells in celiac disease

Autoantibodies against the enzyme transglutaminase 2 (TG2) are characteristic of celiac disease (CeD), and TG2-specific immunoglobulin (Ig) A plasma cells are abundant in gut biopsies of patients. Here, we describe the corresponding population of autoreactive B cells in blood. Circulating TG2-specific IgA cells are present in untreated patients on a gluten-containing diet but not in controls. They are clonally related to TG2-specific small intestinal plasma cells, and they express gut-homing molecules, indicating that they are plasma cell precursors. Unlike other IgA-switched cells, the TG2-specific cells are negative for CD27, placing them in the double-negative (IgD-CD27-) category. They have a plasmablast or activated memory B cell phenotype, and they harbor fewer variable region mutations than other IgA cells. Based on their similarity to naive B cells, we propose that autoreactive IgA cells in CeD are generated mainly through chronic recruitment of naive Bcells via an extrafollicular response involving gluten-specific CD4+ Tcells.

Structural and thermodynamic insights into antibody light chain tetramer formation through 3D domain swapping

Overexpression of antibody light chains in small plasma cell clones can lead to misfolding and aggregation. On the other hand, the formation of amyloid fibrils from antibody light chains is related to amyloidosis. Although aggregation of antibody light chain is an important issue, atomic-level structural examinations of antibody light chain aggregates are sparse. In this study, we present an antibody light chain that maintains an equilibrium between its monomeric and tetrameric states. According to data from X-ray crystallography, thermodynamic and kinetic measurements, as well as theoretical studies, this antibody light chain engages in 3D domain swapping within its variable region. Here, a pair of domain-swapped dimers creates a tetramer through hydrophobic interactions, facilitating the revelation of the domain-swapped structure. The negative cotton effect linked to the β-sheet structure, observed around 215 nm in the circular dichroism (CD) spectrum of the tetrameric variable region, is more pronounced than that of the monomer. This suggests that the monomer contains less β-sheet structures and exhibits greater flexibility than the tetramer in solution. These findings not only clarify the domain-swapped structure of the antibody light chain but also contribute to controlling antibody quality and advancing the development of future molecular recognition agents and drugs.

PCNEO, a New Proficiency Testing Program for Flow Cytometric Analysis of Plasma Cell Neoplasms From the College of American Pathologists Diagnostic Immunology and Flow Cytometry Committee.

In 2018 the College of American Pathologists Diagnostic Immunology and Flow Cytometry Committee designed and implemented a new plasma cell neoplasia flow cytometry proficiency testing program-PCNEO-to allow clinical flow cytometry laboratories to monitor and assess their performance compared with a peer group. To report the results from the first 4 years of the PCNEO program. Program participants were sent 2 sets of challenges per year, each including 1 wet challenge and 2 dry challenges, with associated clinical and laboratory findings. The wet challenges were composed of myeloma cell line specimens (with or without dilution in preserved whole blood) for flow cytometric analysis. The dry (paper) challenges were composed of clinical case summaries and images of flow cytometric test results from various flow cytometry laboratories of committee members. A total of 116 to 145 laboratories from 17 countries enrolled in the proficiency testing program. For the wet challenges, almost all participants (97%-100%; cumulative, 98.2%) correctly identified the presence of neoplastic plasma cell populations based on flow cytometric analysis of undiluted myeloma cell lines. Slightly fewer participants (89.0%-97.4%; cumulative, 95.2%) correctly identified the presence of neoplastic plasma cell populations based on flow cytometric analysis of diluted myeloma cell lines (10% or 50% dilutions into peripheral blood) intended to better represent a typical clinical sample. There was generally agreement among 80% or more of participants for positive or negative staining for CD38, CD138, CD19, CD20, and surface and cytoplasmic κ and λ light chains. Similarly, 84% to 100% of participants were able to correctly identify the presence of neoplastic plasma cell populations in paper challenges, including the presence of small, neoplastic plasma cell populations (0.01%-5.0% clonal plasma cells) and the presence of nonneoplastic plasma cell populations (correctly identified by 91%-96% of participants). Participant performance in the new proficiency testing program was excellent overall, with the vast majority of participants able to perform flow cytometric analysis and identify neoplastic plasma cell populations and to identify small plasma cell clones or expanded populations of reactive plasma cells in dry challenge flow cytometry results. This program will allow laboratories to verify the accuracy of their testing program and test interpretations for the assessment of patients suspected of having a plasma cell neoplasm.

#6598 STUNNING RENAL FUNCTION RECOVERY AFTER TREATMENT WITH DARATUMAMB IN A CASE OF C3 GLOMERULOPATHY WITH MONOCLONAL GAMMOPATHY

Abstract Background and Aims 38 years old man with C3GN linked to Monoclonal Gammopathy recovers from dialysis after treatment with Daratumamb. Case report C3 glomerulonephritis related to monoclonal gammopathy is a challenging entity and the efficacy of treatment with Daratumumab is not clearly defined yet. We would like to describe the case of a stunning renal response to Daratumumab in a young man with MGUS and C3 glomerulonephritis. In July 2021 a 38 years old man presented to our nephrology division with full nephrotic syndrome, creatinine 1.2 mg/dl, low C3 and little IgG lambda spike of 2 g/dL on serum electrophoresis. Kidney biopsy revealed a membranoproliferative GN with bright C3 staining by immunofluorescence, no other positive immune-reactant and no masked deposits on pronase digested tissue. Electron microscopy confirmed the presence of subendothelial electron dense deposits. The diagnosis was consistent with C3 glomerulonephritis. Complement genetic test and C3 nephritic factor were negative. Assuming a form of C3GN associated to monoclonal gammopathy (MGRS), a bone marrow biopsy was performed and revealed a small clonal plasma cells population. In November 2021 he was started on velcade/dexamethasone but unfortunately stopped early due to severe side effects. Subsequently he begun cyclophosphamide and steroids without clinical or serological response. In few months renal function rapidly worsened requiring dialysis since April 2022. A repeat kidney biopsy confirmed C3GN with still moderate activity and low chronicity. In May 2022 he was started on Daratumamab/Lenalidome/Dexamethasone. After eight months of dialysis the diuresis progressively increased and the renal function improved so remarkably that dialysis was discontinued since December 2022. At present the patient renal function is stable with creatinine 3.5 mg/dl, proteinuria 3g/L, and monoclonal component decreased to 1.1 g/L from 3.5 g/L. He continues Daratumumab single agent monthly and we have scheduled a further renal biopsy in the next week. To our knowledge this is the first time a patient recovers from dialysis after treatment with Daratumamb for a C3GN linked to a monoclonal gammopathy. It definitely makes this case unique and inspiring for further studies and considerations regardinf this intriguing field of MGRS.

AL AMYLOIDOSIS UPFRONT TREATMENT AND CURRENT AND FUTURE STUDIES

The treatment of AL amyloidosis is based on the elimination of the plasma cell clone. Today, approved therapies include combinations of the anti-CD38 monoclonal antibody daratumumab with bortezomib, cyclophosphamide and dexamethasone (D-VCd); this combination is effective with about 50%-60% of the patients achieving complete hematologic response and about 80% achieving at least a very good partial hematologic response. However, there are still several unmet needs: patients with very advanced cardiac amyloidosis, such as those stage 3B disease, have been excluded from the clinical trials, and they still have a very poor outcome. Second, at least 50% of patients with AL amyloidosis still fails to achieve a clinically significant organ function improvement. Finally, for patients failing to achieve hematologic or organ response or those who relapse after initial response, there is a need for new treatments and novel strategies. Although most treatments for patients with AL amyloidosis come from the myeloma field, not every therapy given for myeloma is suitable for patients with AL amyloidosis. Targeted therapies, such as those targeting BCL2, can be quite effective, since about 50% of AL patients harbor t(11;14). Anti-BCMA targeting therapies are also promising but they need to be further explored in the setting of AL amyloidosis. Experience with cellular therapies and T-cell redirecting therapies is still limited in AL amyloidosis; such therapies could be quite effective in eliminating the small but toxic amyloidogenic plasma cell clone but their toxicity should be explored specifically in patients with AL amyloidosis. An urgent need remains for the treatment of patients with very advanced cardiac involvement, for which even a deep hematologic remission may not be enough. For these patients, regimens with low toxicity and high efficacy should be prioritized and combined with potentially active amyloid targeting therapies. Combinations of non-cardiotoxic, non-nephrotoxic and non-neurotoxic agents should be prioritized, preferably in fixed duration regimens.

Monoclonal gammopathies of renal significance

The term monoclonal gammopathies of renal significance (MGRS) encompasses a group of renal histopathological lesions fulfilling two criteria: (a) they are caused by nephrotoxic monoclonal immunoglobulins and (b) the monoclonal immunoglobulins are produced by small B-cell or plasma cell clones which do not meet the criteria for multiple myeloma or malignant lymphoma. Here, we provide a review of the MGRS definition and related terminology and elaborate on the diagnostic approach and treatment principles from the general physician perspective.

Amyloid beta-related angiitis in a patient with light chain systemic Amyloidosis: A rare co-morbidity. (P9-5.013)

<h3>Objective:</h3> To report a rare comorbidity of amyloid beta-related angiitis (ABRA) and systemic light chain amyloidosis (AL) <h3>Background:</h3> ABRA is a rare central nervous system (CNS) disorder with overlapping features of primary angiitis of the CNS and cerebral amyloid angiopathy. ABRA pathophysiology differs from extremely rare CNS involvement in AL. This is the first report of ABRA and AL comorbidity. <h3>Design/Methods:</h3> Case Report <h3>Results:</h3> A 73 year old Caucasian female with AL, prior autologous stem cell transplantation followed by relapse and daratumumab therapy resulting in complete response, presented with subacute development of headaches, global dysphasia and right sided homonymous hemianopia. Brain magnetic resonance imaging (MRI) demonstrated an increased T2/Fluid attenuated inversion recovery signal along the left parietal occipital cortex with mild restricted diffusion and microhemorrhages. Cerebrospinal fluid (CSF) studies showed: pleocytosis (30 nucleated cells/mm3) consisting of mature granulocytes, small mature lymphocytes and rare plasma cells, no monotypic B-cell, overtly aberrant T-cell, or expanded large granular lymphocyte population, no malignant cells; hyperproteinorachia (214 mg/dL); and no markers of intrathecal immunoglobulin G synthesis. Infectious CSF studies, CSF autoimmune encephalopathy panel and rheumatological work up were unremarkable. Steroid treatment (methylprednisolone, 1000 mg/day for 5 days intravenously, followed by a slow oral taper) led to a resolution in visual field deficit and a significant improvement in speech patterns. New microhemorrhages with new foci of restricted diffusion in the left posterior parietal/occipital region and posterior right centrum semiovale were shown on brain MRI three months later. Brain biopsy was performed with no neurological complications and pathology was consistent with ABRA. Liquid chromatography-tandem mass spectrometry of the brain tissue detected a peptide profile consistent with amyloid-beta precursor type amyloid deposition. The patient continued on oral steroid taper and is starting cyclophosphamide. <h3>Conclusions:</h3> Although ABRA is pathophysiologically distinct from and unrelated to AL, those two conditions may rarely co-exist. <b>Disclosure:</b> Dr. Javed has nothing to disclose. The institution of Dr. Jensen has received research support from ASCO / Conquer Cancer Foundation. The institution of Dr. Jensen has received research support from AHRQ. Dr. A Tuchman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Shattuck Labs. Dr. A Tuchman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. An immediate family member of Dr. Allenzara has received personal compensation for serving as an employee of Atai . An immediate family member of Dr. Allenzara has stock in Atai company stock . An immediate family member of Dr. Ishizawar has received personal compensation for serving as an employee of EMD MilliporeSigma. Dr. Cho has nothing to disclose. Dr. Yap has nothing to disclose. The institution of Dr. Dujmovic Basuroski has received research support from Alexion Pharmaceuticals, Inc. The institution of Dr. Dujmovic Basuroski has received research support from Biogen MA Inc. The institution of Dr. Dujmovic Basuroski has received research support from EMD Serono Research and Development Institute, Inc . The institution of Dr. Dujmovic Basuroski has received research support from Celgene Corporation/Bristol-Myers Squibb. The institution of Dr. Dujmovic Basuroski has received research support from The Bodford Family Transverse Myelitis Center Fund.

THE UNFORTUNATE PERFECT STORM - SEPTIC SHOCK DUE TO CHRONIC IMMUNOSUPPRESIVE MEDICAL THERAPY AND MEDICATION-INDUCED LYMPHOMA

Abstract INTRODUCTION Pharmacological treatment of Crohn's Disease (CD) involves immunomodulators such as adalimumab, a tumor necrosis factor (TNF) inhibitor and azathioprine, a purine analogue. These medications have risks associated with severe illness from infectious etiologies as well as lymphoma development. This is due to the immunosuppressive effect of the medications as well as a chronic inflammatory state(1). Anaplastic large-cell lymphoma (ALCL) is a subtype of non-Hodgkin's lymphoma (NHL). We present a rare case of sepsis and ALCL in a patient on immunomodulator therapy. CASE DESCRIPTION A 31-year-old G1P0 female at 19 weeks gestation with history of Crohn’s disease presents with abdominal pain. Her medications are adalimumab and azathioprine which were started one year ago due to poorly controlled CD resulting in anal fistulas. She was recently treated for right thigh folliculitis. This progressed to abdominal pain and right inguinal lymphadenopathy. She met SIRS criteria on presentation and was admitted to the intensive care unit for respiratory failure requiring intubation. Despite broad-spectrum antibiotics for pneumonia, she remained febrile with an increasing leukocytosis. Blood, lower respiratory, and fungal cultures, acid-fast staining, viral cultures and smears, and urine tests were negative for a source of infection. Commuted tomography (CT) of the abdomen and pelvis was significant for extensive retroperitoneal lymphadenopathy but found no infectious source. An excisional biopsy of the right groin lymph node was a preliminary read as Hodgkin's lymphoma (HL), but the initial immunohistochemical stain was consistent with NHL. Her immunomodulator therapy was stopped due to sepsis and her risk of lymphoma. She subsequently developed septic shock, acute renal failure requiring continuous renal replacement therapy, atrial fibrillation with rapid ventricular response, and suffered a spontaneous vaginal delivery of a 20-week stillborn baby. A final diagnosis of ALCL was confirmed by pathology. The molecular studies were significant for positivity for CD45, CD30, EMA, CD2, CD4, CD25, ALK1, granzyme B, perforin, and TIA1. She was started on brentuximab, cyclophosphamide, and prednisone. DISCUSSION ALCL is a rare subtype of NHL that accounts for roughly one percent of all NHL (3). The development of lymphomas occurs when the TNF alpha subunit binds to the cell surface. This inhibits both the apoptosis pathway and cytokine-mediated inhibition of CD30+ lymphoma cells resulting in cell proliferation (4). There is limited documentation of adalimumab or azathioprine associated ALCL and this association should be studied further. The patient suffered from severe consequences of her immunosuppression from her chronic immunomodulator therapy and immunosuppression from her malignancy resulting in septic shock with multiorgan failure. Right inguinal lymph node biopsy showing atypical large lymphoid infiltrate, background small lymphocytes, plasma cells, and histiocytes. The large atypical cells are characterized by large irregular nuclei with occasional bilobed nuclei and horseshoe-shaped nuclei, multiple small nucleoli, and abundant amphophilic cytoplasm.

Waldenstrom macroglobulinemia with 11q deletion: A rarely diagnosed entity with review of literature

Waldenstrom macroglobulinemia (WM) is a rare, chronic, and indolent B-cell lymphoproliferative disorder characterized by bone marrow infiltration by small lymphocytes, lymphoplasmacytoid cells, and plasma cells along with the presence of a detectable monoclonal immunoglobulin M. It represents 1%–2% of hematological malignancies with an overall incidence of 3–4 cases/million persons/year. Some deletions are associated with a more aggressive IgM gammopathy and have a high probability of symptomatic transformation. 6q deletion, the most common cytogenetic abnormality, which is present in 42% of cases whereas 11q deletion is rare in WM and is present in only 8% of cases. We are presenting a case of a 70-year-old male patient diagnosed as WM with 11q deletion.

Primary cutaneous blastic marginal zone lymphoma: A comprehensive clinical, light microscopic, phenotypic and cytogenetic appraisal

BackgroundPrimary cutaneous marginal zone lymphoma (PCMZL) is a form of indolent lymphoproliferative disease where the disease is largely a cutaneous confined process. It is typically a neoplasm composed of post germinal small B-cells and light chain restricted plasma cells in a background of reactive T-cell hyperplasia and benign germinal centers. Rarely a significant degree of large cell infiltration occurs warranting the categorization as blastic marginal zone lymphoma. Materials and methodsWe reviewed our data base over a time period of 2016 to 2022 for cases diagnosed as blastic MZL. Twelve cases were identified. The clinical records and pathological data were reviewed. ResultsNine of the cases represented de novo forms of blastic MZL while in three cases there was a prior history of MZL. Multifocal cutaneous disease was not uncommon and one quarter of the cases had evidence of extracutaneous dissemination. All patients except three achieved remission with varied therapeutic interventions depending on the extent of the disease ranging from conservative re-excision to chemotherapy. No patient died from lymphoma. Light microscopically, there was evidence of a background of conventional MZL in the majority of cases. The large cell component was typically characterized by multiple micronodular aggregates throughout the dermis although in three cases there was a striking diffuse large cell component as the dominant infiltrate. Phenotypically, a third of the cases showed either CD5 or CD23 positivity amidst neoplastic B cells. Significant staining for BCL-2 was noted in the majority of cases tested while extensive MUM-1 positivity was observed in half of the cases tested. Kappa or lambda light chain restriction was seen in most. The Ki67 proliferation index exceeded 30 % in all cases. There was C-MYC positivity in two cases. While most cases did not detect cytogenetic abnormalities, one case had multiple cytogenetic hits that are associated with diffuse large B cell lymphoma. Next generation sequencing showed a Ten-eleven translocation 2 mutation in the earlier biopsy prior to transformation and in the later biopsy after transformation along with an additional B2M mutation in the transformed biopsy. Both types of mutations are very uncommon but held to contribute to tumor progression in the setting of diffuse large B cell lymphoma. ConclusionBlastic MZL is associated with a more aggressive clinical course. Even when there is disseminated disease patients while not always cured did not have a fatal course in this series. The light microscopic findings are reproducible. The background of MZL, identification of larger cells in significant numbers without a follicle center phenotype, at times expressing CD5 or CD23 with variable positivity for MUM1, BCL-2 and C-MYC and a high proliferation index define the pathology in most. Certain cytogenetic abnormalities and genetic mutations implicated in large cell transformation into a diffuse large B cell lymphoma are seen in blastic MZL with earlier biopsies prior to transformation potentially harboring at risk genetic mutations.

Prognostic Significance of Circulating Plasma Cells Detected By Next Generation Flow Cytometry in Light (AL) Chain Amyloidosis

In light chain (AL) amyloidosis misfolded light chains that are produced by a generally small or moderate plasma cell clone residing in the bone marrow (BM) form amyloid fibrils and cause organ dysfunction. In asymptomatic myeloma (MM) and patients with MGUS, the presence of circulating clonal plasma cells (CPCs) detected by next generation flow cytometry (NGF) is associated with higher risk of progression to symptomatic disease and in patients with symptomatic MM, higher levels of CPCs are associated with poorer prognosis. In an older study in patients with AL amyloidosis, using 6-color flow cytometry and with a limit of detection (LOD) of ~ 0.01%, CPCs were detected in 42% of patients and their presence was associated with poorer prognosis. In the current study we aimed to evaluate the prognostic and biological impact of CPCs in previously untreated patients with AL amyloidosis by using NGF with a LOD of <0.001%. The presence of CPCs was prospectively evaluated in 114 consecutive patients with AL amyloidosis who were diagnosed and treated in the Department of Clinical Therapeutics, Athens, Greece. CPCs were assessed in peripheral blood (PB) according to the Euroflow guidelines, using two independent 8-color panels, both containing CD19-PC7, CD27-BV510, CD38-FITC, CD45-PerCPCy5.5, CD56-PE, CD138-BV421, and additionally CD117-APC and CD81-APCC750 only in the surface tube or CyIgκ-APC and CyIgλ-APCC750 only in the intracytoplasmic tube. A median number of 5 million events (range 3.9x106-6.1x106) were acquired for each tube and median sensitivity level was 2.3x10-6 (range 2-3.1x10-6) The median age of the cohort was 67 years (38-87), 57% were males, 86% had cardiac, 56% renal, 34% soft tissue, 24% PNS and 19% liver involvement. Mayo stage distribution was 13%, 33% and 54% for stages 1, 2 & 3 and renal stage was 20%, 57% & 23% for stages 1, 2 & 3 respectively. Median iFLC and dFLC levels were 299.3 and 288.5 mg/L respectively and median BM infiltration was 10% (range 0-60%). By FISH, 46% had t(11;14), 40% del13q, 29% +1q21, 6% del17p, 2% t(4;14) and 4% t(14;16). Treatment was bortezomib-based in 96% and contained daratumumab in 34%. CPCs were detectable in 64% of patients and their median level in those with detectable CPCs was 0.002% (range 0.0001%-11.4%). Patients with detectable CPCs had higher LDH (p=0.003), iFLCs (p=0.029), BM infiltration (p=0.002) and NTproBNP (p=0.009). Among patients with detectable CPCs, there was also a correlation of their levels with iFLC levels (p<0.001) and BM infiltration (p<0.001). CPCs were more often detectable (81.5% vs 60%, p=0.053) and their levels were also higher (p=0.014) in those with +1q21; there was no association with any other cytogenetic abnormality. Median follow up of the cohort is 2 years. There was no difference in the OS (2-year OS 65% vs 63%) or in early mortality for patients with or without detectable CPCs (p=0.965). Due to the high sensitivity of NGF in the detection of CPCs, we also evaluated different cutoffs of CPCs for their possible prognostic impact, including cutoffs proposed in the earlier study and in patients with newly diagnosed symptomatic MM (0.01%), but we found no prognostic impact on OS in our patients with AL amyloidosis (2-year OS:55% vs 66%, p=0.374). Higher BM infiltration has been associated with worse outcome in patients with AL amyloidosis: in bivariate analysis CPCs>0.01% overcame the prognostic impact of higher BM infiltration, indicating that CPCs is a more sensitive biomarker of tumor burden in patients with AL amyloidosis. Even after adjustment for Mayo stage the presence of CPCs or of CPCs >0.01% were not prognostically significant. However, patients with CPCs>0.01% had a lower probability of hematologic CR/VGPR at 1 month (23% vs 56%, p=0.03) and at 3 months (44% vs 76%, p=0.043) from start of therapy. In conclusion, circulating clonal plasma cells can be detected in the majority of patients with AL amyloidosis with more sensitive NGF methods. Their presence is associated with higher FLC levels and BM infiltration and adverse prognostic features such as higher NTproBNP level, and a lower probability of deep hematologic response at 1 and 3 months after start of therapy. However, in the era of modern therapies, CPCs do not seem to independently affect the prognosis of patients with AL amyloidosis, which is dominated by the degree of cardiac dysfunction.

A 69-YEAR-OLD MAN WITH HEAVY ASBESTOS EXPOSURE, DYSPNEA, AND PLEURAL SOFT-TISSUE THICKENING

A 69-YEAR-OLD MAN WITH HEAVY ASBESTOS EXPOSURE, DYSPNEA, AND PLEURAL SOFT-TISSUE THICKENING

Une maladie de Rosai–Dorfman–Destombes de présentation laryngée trompeuse

Rosai-Dorfman-Destombes disease is a rare non-Langerhansian cell histiocytosis characterized by the accumulation of large activated histiocytes in the affected tissues with images of emperipolesis. The diagnosis is not really problematic in the classical forms, with a lymph node presentation, whose histology is very suggestive. However, it can be much more difficult in the extra-nodal forms, which are misleading in both their clinical and histological presentation. We report here a case illustrating this diagnostic difficulty. Firstly, clinically, the disease was revealed by an unusual laryngeal location, responsible for acute obstructive respiratory distress and requiring urgent surgical management. Secondly, histologically, the diagnosis was not evoked in the first instance by analysis of the laryngeal lesion. Indeed, there was a not specific appearing polymorphic infiltrate, associating small lymphocytes, plasma cells and numerous histiocytes, without evidence for a lymphoma after immunohistochemistry and lymphocyte clonality analysis. However, after re-examination of the slides, the histiocytes sometimes appeared large or xanthomised and have a PS100+, CD1a-, langerhine- phenotype, with rare images of emperipolesis. These aspects finally suggested the diagnosis of Rosai-Dorfman-Destombes disease, then confirmed by a cervical lymph node biopsy showing characteristic histological features. Simultaneously, NGS analysis of the laryngeal lesion showed a mutation in the MAP2K1 gene, in accordance with the diagnosis. The patient was treated with revlimid and dexamethasone for 6 months, with complete remission, and is currently undergoing maintenance treatment with revlimid.

Adult-onset severe acral angiokeratoma-like pseudolymphoma: A case report and review of the literature.

Adult-onset severe acral angiokeratoma-like pseudolymphoma: A case report and review of the literature.

Молекулярні механізми патогенезу автоімунного тиреоїдиту Хашимото (огляд літератури)

The purpose of the study was to systematize and analyze material of recent studies on molecular mechanisms of pathogenesis of autoimmune Hashimoto's thyroiditis. Materials and methods. Analytical and bibliosemantic methods were used in the study. Results and discussion. Autoimmune Hashimoto's thyroiditis is a chronic inflammatory disease of the thyroid gland of autoimmune genesis in which impaired tolerance to thyroid autoantigens results in chronic progressive lymphoid infiltration followed by gradual destruction of thyroid parenchyma. The disease is more often observed at the age of 45-65 years and is multifactorial – both genetic predisposition and environmental factors contribute to its development. The ratio of female to male patients is approximately 10-20:1, and in recent years, the prevalence of autoimmune Hashimoto's thyroiditis has increased more than tenfold. On morphological examination, the section of the thyroid is diffusely enlarged, the surface of the section is pale, yellow-brown in color, dense and nodular. Microscopic examination reveals numerous large mononuclear inflammatory infiltrates in the parenchyma, consisting of small lymphocytes and plasma cells, well-formed germinal centers. A twin method is used to assess the degree of contribution of genetic and environmental factors. Studies demonstrate significantly greater concordance in monozygotic twins than in dizygotic twins, confirming the important role of genetic factors in the etiology. Among the main immune mechanisms of damage are: direct action of CD8+ cytotoxic T cells on thyrocytes by binding through the Fas-receptor – Fas ligand system; the influence of cytokines, in particular – interferon γ, produced by TH1 cells and leading to macrophage activation with subsequent damage to follicles, antibody-dependent cell-mediated cytotoxicity, in which Fc fragments of antibodies previously bound to thyroid cells are binding sites to cells that commit killing, in particular – to the natural killer cells. In terms of thyroid cell damage, cytokines produced by the lymphocytic infiltrate play a key role. These include differentiation, signal transduction, and stimulation of other cells to release proinflammatory mediators or synthesize antibodies. Their ability to stimulate the thyroid cells themselves to release inflammatory mediators should be noted, thereby enhancing and perpetuating the autoimmune process. Researchers have identified other mechanisms, and the ratio of their contribution to the overall pathological process is a matter of debate and may vary from patient to patient. One explanation may be the multifactorial nature of the disease. In particular, different genetic mutations can lead to different disorders of intracellular and intercellular signaling, but the resulting factor will be one – immune autoaggression. Conclusion. The pathogenesis of autoimmune Hashimoto's thyroiditis is complex and multifaceted, involving both humoral and cellular immunity. The disease may be provoked both by mutations in the mechanisms of immune regulation, by mutations in the thyroid cells themselves, and by environmental factors

Waldenstrom Macroglobulinaemia with Signet Ring Cells: A Case Report

Waldenstrom Macroglobulinemia (WM) is an indolent lymphoproliferative disorder characterised by Immunoglobulin M (IgM) production and neoplastic lymphoid infiltrate. The morphology of the neoplastic cells show spectrum of maturation characterised by small lymphocytes, lymphoplasmacytoid cells and plasma cells. The infiltrate is predominantly lymphoid with relatively small population of plasma cells. The plasma cell morphology is commonly of mature type with basophilic cytoplasm, eccentric nucleus with clumped chromatin and perinuclear halo (hof). But incidence of signet ring cells in WM is very rare and only one case has been reported till date. Here, authors report an interesting case of a 61-year-old man who presented with on and off chest pain and later diagnosed as WM with signet ring cells. On examination, the patient was found to have anaemia and lymphadenopathy. Bone marrow aspirate cytology showed hypercellular particles and scattered signet ring like plasma cells with large globular cytoplasmic inclusions. Flow Cytometry (FCM) established the diagnosis by demonstrating the clonal nature of plasma cells and B-lymphoid cells. Immunofixation confirmed the presence of monoclonal protein of IgM lambda type. The cytoplasmic content in these signet ring plasma cells is probably the accumulated IgM due to the defect in releasing. Clustering of these signet ring cells in marrow may raise a suspicion of metastatic adenocarcinoma and should not be misinterpreted.

Lymphoplasmacytic lymphoma: a clinicopathological and prognostic analysis of 27 cases

Objective: To study the clinical manifestations, pathologic features, diagnosis and differential diagnosis, treatment and prognosis of lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (LPL/WM). Methods: Twenty-seven cases of LPL from January 2016 to December 2020 at Guangdong Provincial People's Hospital were collected. The clinical data, histomorphology, immunophenotype, MYD88 L265P mutation, treatment and prognosis were analyzed retrospectively. Results: There were 19 males and 8 female patients, with median age of 63 years. The most common initial symptoms were fatigue related to anemia. Bone marrow was involved in all cases, lymphadenopathy was seen in 11 cases and splenomegaly in 10 cases. Monoclonal IgM type protein was detected in 25 cases, meeting the diagnostic criteria of WM. Microscopically, bone marrow and lymph nodes were infiltrated by small lymphocytes, plasmacytoid lymphocytes or plasma cells. The cells expressed pan B-cell markers and showed immunoglobulin light chain restriction. There was no expression of CD5, and low expression of CD23 and CD10; Ki-67 index was usually low. The positive rate of MYD88 L265P mutation was 73.9% (17/23). Most of the patients were treated with rituximab combined with alkylating agents, nucleoside analogues or immunomodulators, and the few patients with relapse or progression were treated with Ibutinib. During the 3-168 months' follow-up period, recurrence or progression were seen in nine cases. Thrombocytopenia, elevated β2-microglobulin and high-risk group were associated with recurrence or progression of the disease (P<0.05). The overall survival (OS) and progression-free survival (PFS) of the high-risk patients were significantly lower than those of the low-medium risk patients (P<0.05). Conclusions: LPL/WM is an exclusive diagnosis; the detection of MYD88 L265P mutation has high diagnostic value, but it is not specific. These cases should be assessed comprehensively for their clinical manifestation, serum IgM protein level and immunophenotype. The overall prognosis of LPL/WM is good, but there are still a small number of high-risk patients with rapid progress, and so the symptomatic patients should be diagnosed accurately and treated in a timely manner.